A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2

Abstract

Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enrichment on gene promoters in prostate cancer.To study the impact of this enrichment, a transcriptomic analysis with TaqMan Low Density Array (TLDA) of several genes was studied on prostate biopsies divided into three clinical grades: normal (n = 23) and two tumor groups that differed in their aggressiveness (Gleason score ≤ 7 (n = 20) and >7 (n = 19)). ANOVA demonstrated that expression of the gene set was upregulated in tumors and correlated with Gleason score, thus discriminating between the three clinical groups. Six genes involved in key cellular processes stood out: JMJD3, EZH2, MGMT, TRA2A, U2AF1 and RPS6KA2. Chromatin immunoprecipitation demonstrated collocation of EZH2 and JMJD3 on gene promoters that was dependent on disease stage. Gene set expression was also evaluated on prostate cancer cell lines (DU 145, PC-3 and LNCaP) treated with an inhibitor of JMJD3 (GSK-J4) or EZH2 (DZNeP) to study their involvement in gene regulation. Results showed a difference in GSK-J4 sensitivity under PTEN status of cell lines and an opposite gene expression profile according to androgen status of cells.In summary, our data describe the impacts of JMJD3 and EZH2 on a new gene signature involved in prostate cancer that may help identify diagnostic and therapeutic targets in prostate cancer.

JMJD3 in the regulation of human diseases

“…JMJD3 also activated key oncogenes in gene of phosphate and tension homology deleted on chromosome ten (PTEN) and androgen receptor (AR) pathways participated in prostate cancer. JMJD3 was a potential new biomarker for prognosis (Daures et al 2018). The B cell receptor (BCR) signaling pathway represents a key component of normal B cell survival during the whole development.…”

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

“…Treatment of brain stem glioma cells with GSK-J4 was able to reverse this downregulation of H3K27 methylation, at least in part via inhibition of KDM6B, and inhibited cell and tumor growth 152 . GSK-J4 has also been shown to be effective in diffuse large B-cell lymphoma, as a chemotherapy-sensitizing agent 155 , AML 146 , breast cancer 156 , taxane/platin-resistant lung cancer 123 , and prostate cancer 157 , including its castration-resistant subtype 158 .…”

TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer

“…About 25-40 μg of extracted proteins were resolved by electrophoresis on 8-15% sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE) (Bio-Rad, Hercules, CA, USA). Electro-transfer, blockage of membranes, immunoblotting and immunolabeling were performed using the manufacturer's protocol and the experimental methods developed in our laboratory (20,22). The primary antibodies (Abs) used were: anti-TIP60 Abs (1/500, GTX112197) and anti-P400 Ab (1/500, GTX116689) were purchased from GenTex (CA, USA), anti-H4k12ac Abs (1/750, C15200218, Diagenode) and anti-GAPDH Abs (1/5000, sc-47724, Santa Cruz Biotechnology).…”

“…Breast tumors and their adjacent healthy tissues were crushed at the french press. RNA extracts were obtained using NucleoSpin ® RNA/Protein, Mini kit for RNA, protein purification (Macherey-Nagel, France) and reverse transcription were performed using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems) and Synthesized cDNAs were amplified using TaqMan Gene expression PCR Master Mix (Applied Biosystems) according to the manufacturer's protocol and the experimental methods developed in our laboratory (20,22). The TaqMan Gene Expression assay-on-demand used were TIP60 [Hs00197310_m1] or P400 [Hs01566078_m1] and endogenous control 18S Rrna [Hs99999901_s1].…”